Update on therapeutic mechanism for bone marrow stromal cells in ischemic stroke

Journal of Molecular Neuroscience

Volumn 52, Issue 2, 2014, Pages 177-185

  Wan, Huan ^a   Li, Fangqin ^a   Zhu, Lei ^a   Wang, Jing ^a   Yang, Zizhen ^a   Pan, Yujun ^a  

^a HARBIN MEDICAL UNIVERSITY   (China)

Author keywords

Bone marrow stromal cells; Ischemic stroke; Regeneration; Therapeutic mechanism; Transplantation

Indexed keywords

ANIMALS; BRAIN ISCHEMIA; HUMANS; MESENCHYMAL STEM CELL TRANSPLANTATION; MESENCHYMAL STROMAL CELLS; STROKE;

EID: 84894230118     PISSN: 08958696     EISSN: 15591166     Source Type: Journal    
DOI: 10.1007/s12031-013-0119-0     Document Type: Review

References (92)

1. Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815-1822
2. Bliss TM, Andres RH, Steinberg GK (2010) Optimizing the success of cell transplantation therapy for stroke. Neurobiol Dis 37:275-283
3. Borlongan CV, Lind JG, Dillon-Carter O, Yu G, Hadman M, Cheng C, Carroll J, Hess DC (2004) Bone marrow grafts restore cerebral blood flow and blood brain barrier in stroke rats. Brain Res 1010:108-116
4. Chamorro A, Meisel A, Planas AM, Urra X, van de Beek D, Veltkamp R (2012) The immunology of acute stroke. Nat Rev Neurol 8:401-410
5. Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M (2001) Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32:1005-1011
6. Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, Lu M, Gautam SC, Chopp M (2003a) Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73:778-786
7. Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, Lu M, Zhu Z, Chopp M (2003b) Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 92:692-699
8. Chen J, Li Y, Zhang R, Katakowski M, Gautam SC, Xu Y, Lu M, Zhang Z, Chopp M (2004) Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis. Brain Res 1005:21-28
9. Chen JR, Cheng GY, Sheu CC, Tseng GF, Wang TJ, Huang YS (2008) Transplanted bone marrow stromal cells migrate, differentiate and improve motor function in rats with experimentally induced cerebral stroke. J Anat 213:249-258
10. Chen J, Ye X, Yan T, Zhang C, Yang XP, Cui X, Cui Y, Zacharek A, Roberts C, Liu X, Dai X, Lu M, Chopp M (2011) Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats. Stroke 42:3551-3558
11. Cui X, Chen J, Zacharek A, Li Y, Roberts C, Kapke A, Savant-Bhonsale S, Chopp M (2007) Nitric oxide donor upregulation of stromal cell-derived factor-1/chemokine (CXC motif) receptor 4 enhances bone marrow stromal cell migration into ischemic brain after stroke. Stem Cells 25:2777-2785
12. Cui X, Chen J, Zacharek A, Roberts C, Savant-Bhonsale S, Chopp M (2008) Treatment of stroke with (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1, 2-diolate and bone marrow stromal cells upregulates angiopoietin-1/Tie2 and enhances neovascularization. Neuroscience 156:155-164
13. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315-317
14. Drela E, Stankowska K, Kulwas A, Rosc D (2012) Endothelial progenitor cells in diabetic foot syndrome. Adv Clin Exp Med 21:249-254
15. Engelhardt B, Sorokin L (2009) The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31:497-511
16. Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS Jr (2009) Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 18:683-692
17. Galmiche MC, Koteliansky VE, Briere J, Herve P, Charbord P (1993) Stromal cells from human long-term marrow cultures are mesenchymal cells that differentiate following a vascular smooth muscle differentiation pathway. Blood 82:66-76
18. Gopurappilly R, Pal R, Mamidi MK, Dey S, Bhonde R, Das AK (2011) Stem cells in stroke repair: current success and future prospects. CNS Neurol Disord Drug Targets 10:741-756
19. Guo F, Lv S, Lou Y, Tu W, Liao W, Wang Y, Deng Z (2012) Bone marrow stromal cells enhance the angiogenesis in ischaemic cortex after stroke: involvement of notch signalling. Cell Biol Int 36:997-1004
20. Guzman R, Choi R, Gera A, De Los Angeles A, Andres RH, Steinberg GK (2008) Intravascular cell replacement therapy for stroke. Neurosurg Focus 24:E15
21. Haynesworth SE, Baber MA, Caplan AI (1992) Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies. Bone 13:69-80
22. Herzog EL, Chai L, Krause DS (2003) Plasticity of marrow-derived stem cells. Blood 102:3483-3493
23. Hicks A, Jolkkonen J (2009) Challenges and possibilities of intravascular cell therapy in stroke. Acta Neurobiol Exp (Wars) 69:1-11
24. Hokari M, Kuroda S, Chiba Y, Maruichi K, Iwasaki Y (2009) Synergistic effects of granulocyte-colony stimulating factor on bone marrow stromal cell transplantation for mice cerebral infarct. Cytokine 46:260-266
25. Honmou O, Onodera R, Sasaki M, Waxman SG, Kocsis JD (2012) Mesenchymal stem cells: therapeutic outlook for stroke. Trends Mol Med 18:292-297
26. Ito M, Kuroda S, Sugiyama T, Maruichi K, Kawabori M, Nakayama N, Houkin K, Iwasaki Y (2012) Transplanted bone marrow stromal cells protect neurovascular units and ameliorate brain damage in stroke-prone spontaneously hypertensive rats. Neuropathology 32:522-533
27. Javazon EH, Beggs KJ, Flake AW (2004) Mesenchymal stem cells: paradoxes of passaging. Exp Hematol 32:414-425
28. Jin K, Sun Y, Xie L, Mao XO, Childs J, Peel A, Logvinova A, Banwait S, Greenberg DA (2005) Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiol Dis 18:366-374
29. Kawabori M, Kuroda S, Sugiyama T, Ito M, Shichinohe H, Houkin K, Kuge Y, Tamaki N (2012) Intracerebral, but not intravenous, transplantation of bone marrow stromal cells enhances functional recovery in rat cerebral infarct: an optical imaging study. Neuropathology 32:217-226
30. Kawabori M, Kuroda S, Ito M, Shichinohe H, Houkin K, Kuge Y, Tamaki N (2013) Timing and cell dose determine therapeutic effects of bone marrow stromal cell transplantation in rat model of cerebral infarct. Neuropathology 33:140-148
31. Keimpema E, Fokkens MR, Nagy Z, Agoston V, Luiten PG, Nyakas C, Boddeke HW, Copray JC (2009) Early transient presence of implanted bone marrow stem cells reduces lesion size after cerebral ischaemia in adult rats. Neuropathol Appl Neurobiol 35:89-102
32. Kleinschnitz C, Schwab N, Kraft P, Hagedorn I, Dreykluft A, Schwarz T, Austinat M, Nieswandt B, Wiendl H, Stoll G (2010) Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 115:3835-3842
33. Komatsu K, Honmou O, Suzuki J, Houkin K, Hamada H, Kocsis JD (2010) Therapeutic time window of mesenchymal stem cells derived from bone marrow after cerebral ischemia. Brain Res 1334:84-92
34. Kondziolka D, Steinberg GK, Wechsler L, Meltzer CC, Elder E, Gebel J, Decesare S, Jovin T, Zafonte R, Lebowitz J, Flickinger JC, Tong D, Marks MP, Jamieson C, Luu D, Bell-Stephens T, Teraoka J (2005) Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg 103:38-45
35. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F (2003) Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 101:3722-3729
36. Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105:369-377
37. Kurozumi K, Nakamura K, Tamiya T, Kawano Y, Kobune M, Hirai S, Uchida H, Sasaki K, Ito Y, Kato K, Honmou O, Houkin K, Date I, Hamada H (2004) BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol Ther 9:189-197
38. Law S, Chaudhuri S (2013) Mesenchymal stem cell and regenerative medicine: regeneration versus immunomodulatory challenges. Am J Stem Cells 2:22-38
39. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O (2003) HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31:890-896
40. Li Y, Chopp M (2010) Cellular approaches to stroke recovery. In: Cramer SC, Nudo RJ (eds) Brain repair after stroke. Cambridge University Press, Cambridge, p 267
41. Li Y, Chopp M, Chen J, Wang L, Gautam SC, Xu YX, Zhang Z (2000) Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab 20:1311-1319
42. Li Y, Chen J, Wang L, Lu M, Chopp M (2001) Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology 56:1666-1672
43. Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, Katakowski M, Zhang LJ, Lu M, Janakiraman N, Chopp M (2002) Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59:514-523
44. Li Y, McIntosh K, Chen J, Zhang C, Gao Q, Borneman J, Raginski K, Mitchell J, Shen L, Zhang J, Lu D, Chopp M (2006) Allogeneic bone marrow stromal cells promote glial-axonal remodeling without immunologic sensitization after stroke in rats. Exp Neurol 198:313-325
45. Liu N, Chen R, Du H, Wang J, Zhang Y, Wen J (2009) Expression of IL-10 and TNF-alpha in rats with cerebral infarction after transplantation with mesenchymal stem cells. Cell Mol Immunol 6:207-213
46. Liu Z, Li Y, Zhang ZG, Cui X, Cui Y, Lu M, Savant-Bhonsale S, Chopp M (2010) Bone marrow stromal cells enhance inter- and intracortical axonal connections after ischemic stroke in adult rats. J Cereb Blood Flow Metab 30:1288-1295
47. Liu N, Deguchi K, Yamashita T, Liu W, Ikeda Y, Abe K (2012a) Intracerebral transplantation of bone marrow stromal cells ameliorates tissue plasminogen activator-induced brain damage after cerebral ischemia in mice detected by in vivo and ex vivo optical imaging. J Neurosci Res 90:2086-2093
48. Liu Y, Lai WH, Liao SY, Siu CW, Yang YZ, Tse HF (2012b) Lack of cardiac nerve sprouting after intramyocardial transplantation of bone marrow-derived stem cells in a swine model of chronic ischemic myocardium. J Cardiovasc Transl Res 5:359-364
49. Mimura T, Dezawa M, Kanno H, Yamamoto I (2005) Behavioral and histological evaluation of a focal cerebral infarction rat model transplanted with neurons induced from bone marrow stromal cells. J Neuropathol Exp Neurol 64:1108-1117
50. Misra V, Ritchie MM, Stone LL, Low WC, Janardhan V (2012) Stem cell therapy in ischemic stroke: role of IV and intra-arterial therapy. Neurology 79:S207-S212
51. Modo M, Stroemer RP, Tang E, Patel S, Hodges H (2002) Effects of implantation site of stem cell grafts on behavioral recovery from stroke damage. Stroke 33:2270-2278
52. Omori Y, Honmou O, Harada K, Suzuki J, Houkin K, Kocsis JD (2008) Optimization of a therapeutic protocol for intravenous injection of human mesenchymal stem cells after cerebral ischemia in adult rats. Brain Res 1236:30-38
53. Onda T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD (2008) Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J Cereb Blood Flow Metab 28:329-340
54. Ooboshi H, Ibayashi S, Shichita T, Kumai Y, Takada J, Ago T, Arakawa S, Sugimori H, Kamouchi M, Kitazono T, Iida M (2005) Postischemic gene transfer of interleukin-10 protects against both focal and global brain ischemia. Circulation 111:913-919
55. Pavlichenko N, Sokolova I, Vijde S, Shvedova E, Alexandrov G, Krouglyakov P, Fedotova O, Gilerovich EG, Polyntsev DG, Otellin VA (2008) Mesenchymal stem cells transplantation could be beneficial for treatment of experimental ischemic stroke in rats. Brain Res 1233:203-213
56. Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T (2002) G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 3:687-694
57. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143-147
58. Rosell A, Cuadrado E, Ortega-Aznar A, Hernandez-Guillamon M, Lo EH, Montaner J (2008) MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 39:1121-1126
59. Ruff CA, Wilcox JT, Fehlings MG (2012) Cell-based transplantation strategies to promote plasticity following spinal cord injury. Exp Neurol 235:78-90
60. Scheibe F, Ladhoff J, Huck J, Grohmann M, Blazej K, Oersal A, Baeva N, Seifert M, Priller J (2012) Immune effects of mesenchymal stromal cells in experimental stroke. J Cereb Blood Flow Metab 32:1578-1588
61. Shen LH, Li Y, Chen J, Zhang J, Vanguri P, Borneman J, Chopp M (2006) Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. Neuroscience 137:393-399
62. Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M (2007) Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 27:6-13
63. Shen LH, Ye M, Ding XS, Han Q, Zhang C, Liu XF, Huang H, Wu EB, Huang HF, Gu XS (2012) Protective effects of MCI-186 on transplantation of bone marrow stromal cells in rat ischemic stroke model. Neuroscience 223:315-324
64. Shichinohe H, Kuroda S, Lee JB, Nishimura G, Yano S, Seki T, Ikeda J, Tamura M, Iwasaki Y (2004) In vivo tracking of bone marrow stromal cells transplanted into mice cerebral infarct by fluorescence optical imaging. Brain Res Brain Res Protoc 13:166-175
65. Shyu WC, Chen CP, Lin SZ, Lee YJ, Li H (2007) Efficient tracking of non-iron-labeled mesenchymal stem cells with serial MRI in chronic stroke rats. Stroke 38:367-374
66. Shyu WC, Lin SZ, Yen PS, Su CY, Chen DC, Wang HJ, Li H (2008) Stromal cell-derived factor-1 alpha promotes neuroprotection, angiogenesis, and mobilization/homing of bone marrow-derived cells in stroke rats. J Pharmacol Exp Ther 324:834-849
67. Song M, Mohamad O, Gu X, Wei L, Yu SP (2012) Restoration of intracortical and thalamocortical circuits after transplantation of bone marrow mesenchymal stem cells into the ischemic brain of mice. Cell Transplant. doi: 10.3727/096368912X657909
68. Sordi V, Malosio ML, Marchesi F, Mercalli A, Melzi R, Giordano T, Belmonte N, Ferrari G, Leone BE, Bertuzzi F, Zerbini G, Allavena P, Bonifacio E, Piemonti L (2005) Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood 106:419-427
69. Steiner B, Roch M, Holtkamp N, Kurtz A (2012) Systemically administered human bone marrow-derived mesenchymal stem home into peripheral organs but do not induce neuroprotective effects in the MCAo-mouse model for cerebral ischemia. Neurosci Lett 513:25-30
70. Walczak P, Zhang J, Gilad AA, Kedziorek DA, Ruiz-Cabello J, Young RG, Pittenger MF, van Zijl PC, Huang J, Bulte JW (2008) Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke 39:1569-1574
71. Wang L, Li Y, Chen J, Gautam SC, Zhang Z, Lu M, Chopp M (2002) Ischemic cerebral tissue and MCP-1 enhance rat bone marrow stromal cell migration in interface culture. Exp Hematol 30:831-836
72. Wang Y, Deng Y, Zhou GQ (2008) SDF-1alpha/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. Brain Res 1195:104-112
73. Wang Y, Huang J, Li Y, Yang GY (2012) Roles of chemokine CXCL12 and its receptors in ischemic stroke. Curr Drug Targets 13:166-172
74. Wang L, Lin Z, Shao B, Zhuge Q, Jin K (2013a) Therapeutic applications of bone marrow-derived stem cells in ischemic stroke. Neurol Res 35:470-478
75. Wang X, Bie R, Sun Y, Wu Z, Zhou M, Cao R, Xie L, Zhang D (2013b) The architecture of an automatic eHealth platform with mobile client for cerebrovascular disease detection. JMIR Mhealth Uhealth 1:e20
76. Wei L, Fraser JL, Lu ZY, Hu X, Yu SP (2012) Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis 46:635-645
77. Willing A, Shahaduzzaman M (2013) Delivery routes for cell therapy in stroke. In: Jolkkonen J, Walczak P (eds) Cell-based therapies in stroke. Springer, Vienna, pp 15-28
78. Wu J, Sun Z, Sun HS, Weisel RD, Keating A, Li ZH, Feng ZP, Li RK (2008) Intravenously administered bone marrow cells migrate to damaged brain tissue and improve neural function in ischemic rats. Cell Transplant 16:993-1005
79. Xin H, Li Y, Chen X, Chopp M (2006) Bone marrow stromal cells induce BMP2/4 production in oxygen-glucose-deprived astrocytes, which promotes an astrocytic phenotype in adult subventricular progenitor cells. J Neurosci Res 83:1485-1493
80. Xin H, Li Y, Shen LH, Liu X, Hozeska-Solgot A, Zhang RL, Zhang ZG, Chopp M (2011) Multipotent mesenchymal stromal cells increase tPA expression and concomitantly decrease PAI-1 expression in astrocytes through the sonic hedgehog signaling pathway after stroke (in vitro study). J Cereb Blood Flow Metab 31:2181-2188
81. Yasuhara T, Matsukawa N, Hara K, Maki M, Ali MM, Yu SJ, Bae E, Yu G, Xu L, McGrogan M, Bankiewicz K, Case C, Borlongan CV (2009) Notch-induced rat and human bone marrow stromal cell grafts reduce ischemic cell loss and ameliorate behavioral deficits in chronic stroke animals. Stem Cells Dev 18:1501-1514
82. Yilmaz G, Vital S, Yilmaz CE, Stokes KY, Alexander JS, Granger DN (2011) Selectin-mediated recruitment of bone marrow stromal cells in the postischemic cerebral microvasculature. Stroke 42:806-811
83. Yoo SW, Kim SS, Lee SY, Lee HS, Kim HS, Lee YD, Suh-Kim H (2008) Mesenchymal stem cells promote proliferation of endogenous neural stem cells and survival of newborn cells in a rat stroke model. Exp Mol Med 40:387-397
84. Yu X, Chen D, Zhang Y, Wu X, Huang Z, Zhou H, Zhang Z (2012) Overexpression of CXCR4 in mesenchymal stem cells promotes migration, neuroprotection and angiogenesis in a rat model of stroke. J Neurol Sci 316:141-149
85. Zacharek A, Shehadah A, Chen J, Cui X, Roberts C, Lu M, Chopp M (2010) Comparison of bone marrow stromal cells derived from stroke and normal rats for stroke treatment. Stroke 41:524-530
86. Zhang J, Li Y, Chen J, Yang M, Katakowski M, Lu M, Chopp M (2004) Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Res 1030:19-27
87. Zhang C, Li Y, Chen J, Gao Q, Zacharek A, Kapke A, Chopp M (2006) Bone marrow stromal cells upregulate expression of bone morphogenetic proteins 2 and 4, gap junction protein connexin-43 and synaptophysin after stroke in rats. Neuroscience 141:687-695
88. Zhao LR, Duan WM, Reyes M, Keene CD, Verfaillie CM, Low WC (2002) Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol 174:11-20
89. Zhao MZ, Nonoguchi N, Ikeda N, Watanabe T, Furutama D, Miyazawa D, Funakoshi H, Kajimoto Y, Nakamura T, Dezawa M, Shibata MA, Otsuki Y, Coffin RS, Liu WD, Kuroiwa T, Miyatake S (2006) Novel therapeutic strategy for stroke in rats by bone marrow stromal cells and ex vivo HGF gene transfer with HSV-1 vector. J Cereb Blood Flow Metab 26:1176-1188
90. Zhao Y, Guan Y, Xu Y, Li Y, Wu W (2012) Sodium ferulate combined with bone marrow stromal cell treatment ameliorating rat brain ischemic injury after stroke. Brain Res 1450:157-165
91. Zheng W, Honmou O, Miyata K, Harada K, Suzuki J, Liu H, Houkin K, Hamada H, Kocsis JD (2010) Therapeutic benefits of human mesenchymal stem cells derived from bone marrow after global cerebral ischemia. Brain Res 1310:8-16
92. Zhou S (2011) From bone to brain: human skeletal stem cell therapy for stroke. Cent Nerv Syst Agents Med Chem 11:157-163